In laboratory medicine, standardization ensures the traceability of laboratory tests to certified reference materials (CRM) and primary reference measurement procedures (RMPs). This practice is integral to improving test accuracy, enabling inter-laboratory comparability, and fostering uniform clinical decision-making, which elevates the overall quality of patient care. The standardization of laboratory tests requires sustained collaboration among all stakeholders, including in vitro diagnostics (IVD) manufacturers, clinical laboratories, regulatory bodies, and professional organizations.

The creatinine standardization program, launched in 2006 by the National Kidney Disease Education Program (NKDEP) and the International Federation of Clinical Chemistry (IFCC), was a key milestone [2]. In 2007, the introduction of standard reference material 967, an isotope dilution mass spectrometry (IDMS)-traceable creatinine values, allowed global IVD manufacturers to develop and clinical laboratories to adopt IDMS-traceable calibrators. Before standardization, creatinine assays showed significant variability, with biases ranging from –0.06 to 0.31 mg/dL, depending more on the manufacturer than on the assay method [3]. After standardization, inter-manufacturer variability was decreased, and biases of 0.1–0.2 mg/dL were effectively corrected, improving eGFR reliability [4].

Tracking the adoption of standardized calibrators for creatinine assays in Korea has been challenging. The Korean Association of External Quality Assessment Service (KEQAS) accuracy-based creatinine (ABCr) proficiency testing (PT) program, launched in 2011, provides insights into bias reduction and the gradual adoption of standardized calibrators [5]. The mean bias for creatinine assays was 10.8% in 2011 but significantly decreased to 4.0% in 2014, 2.0% in 2017, –0.6% in 2020, and 0.8% in 2023 [5, 6]. While the KEQAS does not track which calibrators the participating laboratories used, the observed reduction in positive biases highlights the timeline of standardized calibrator adoption. Roche demonstrated consistently low biases since 2011, when it introduced standardized calibrators, whereas Beckman Coulter and Siemens began supplying standardized calibrators around 2014 [5]. Open systems using mixed reagents, calibrators, and instruments from various manufacturers add complexity to tracking standardization. Since 2017, major reagent manufacturers in Korea have participated in a quality certification program for creatinine assay products, co-hosted by the Korean Society for Laboratory Medicine (KSLM) and the Korea Disease Control and Prevention Agency [7]. This program mandates the use of standardized calibrators. By 2024, 16 manufacturers had certified 87 IDMS-traceable calibrator–reagent combinations.

Standardized creatinine assays do not ensure consistent bias across clinical laboratories. According to 2023 KEQAS PT data, only Roche and Beckman Coulter met the optimal bias criterion (2.1%) set by the European Federation of Clinical Chemistry and Laboratory Medicine, while Shenzhen Mindray and Shinwha Medi achieved desirable bias (4.2%), and Sekisui Medical, minimum bias (6.3%) [6]. The 2024 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend a desirable bias of <3.7% [8], but only 9.1% of KEQAS ABCr PT participants in 2023 met this threshold [6]. These findings highlight the need for continuous efforts to improve assay accuracy in Korean laboratories.

Since 2018, the KEQAS has provided granular data on assay methods. As of 2023, approximately 90% of Korean clinical laboratories employed the Jaffe method (Fig. 1A) despite the KDIGO 2024 guidelines recommending enzymatic methods [8]. Laboratories employing Jaffe methods without compensation reported higher positive biases, particularly in low-concentration samples, a trend that persists (Fig. 1B). Manufacturers are urged to incorporate compensation mechanisms in Jaffe-based reagents to mitigate such biases.

Cystatin C assay standardization, mainly using immunonephelometric or immunoturbidimetric methods, lags behind creatinine. The IFCC introduced CRM ERM-DA471/IFCC in 2010 for calibration [9]. However, its high concentration (5.48 mg/L) limits clinical accuracy. Liquid chromatography-MS-based cystatin C measurement methods exist but lack a certified RMP as of 2024, leaving standardization incomplete [10]. High costs further hinder adoption, with only 111 institutions in the KEQAS for cystatin C compared to 1,840 for creatinine in 2024. Wider use of cystatin C measurements in Korea will require more time.

The 2024 KDIGO guidelines recommend creatinine-based eGFR as the primary GFR assessment, supplemented by cystatin C measurement or measured (m)GFR using exogenous markers when inaccuracies are suspected [8]. The historical trajectory of eGFR equations reveals substantial advancements. The Cockcroft–Gault equation (1976) was foundational but was succeeded by the Modification of Diet in Renal Disease (MDRD) equation (1999), which demonstrated enhanced accuracy for GFR estimation in chronic kidney disease. Following creatinine standardization, the IDMS-traceable MDRD 4-variable equation was introduced, but it retained the inherent limitations of creatinine as a biomarker. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, developed using a larger and more diverse cohort, was introduced in 2009 [11]. The 2021 CKD-EPI equation excluded race as a variable, addressing concerns over its relevance and equity in clinical applications [12]. Despite this advancement, the 2009 CKD-EPI equation offers less biased GFR estimates than the 2021 version (1.8 vs. 4.8 [13] and 2.2 vs. 5.4 mL/min/1.73m² [14], respectively), suggesting that the 2009 CKD-EPI equation remains more suitable for Koreans.

The full-age-spectrum (FAS) equation was introduced in Europe in 2016 to estimate GFR across individuals aged ≥2 yrs. In 2021, it was refined into the Modified FAS (also known as the European Kidney Function Consortium [EKFC]) equation using data from multiple European cohorts [15]. While the US and Europe advocate for their respective eGFR equations, Europe has resisted adopting the 2021 CKD-EPI equation, emphasizing regional validation [16]. The 2024 KDIGO guidelines recognize three primary eGFR equations: 2021 CKD-EPI, EKFC, and region-specific adaptations, reflecting a shift from the 2012 KDIGO guidelines, which primarily endorsed the 2009 CKD-EPI equation, highlighting the need to adapt eGFR estimation methods to diverse populations [8]. Further studies are required to evaluate these equations in Korea.

The development of cystatin C-based eGFR equations has paralleled advancements in creatinine-based methods. Cystatin C, alone or in combination with creatinine, improves the accuracy of eGFR estimates by mitigating creatinine’s dependence on muscle mass, its susceptibility to tubular secretion, and analytical interferences [8]. The 2021 CKD-EPI equation inspired the development of the 2021 CKD-EPIcr-cys equation [11]. Recently, the EKFC eGFRcys equation was introduced, eliminating race and sex as variables and addressing biases inherent in previous models [17].

The current state of eGFR calculation methods in Korean laboratories can be analyzed through the KEQAS ABCr PT program. Until 2022, laboratories could primarily report only two equations: the CKD-EPI (2009) and MDRD (IDMS-traceable). Expanded options, including newer equations, became available in 2023. By the second round of KEQAS 2024 ABCr PT, 732 of 1,840 laboratories (40.2%) performing creatinine testing reported eGFR, reflecting an increase from 34.2% in 2020 (Fig. 2A). Despite this progress, eGFR reporting rates in Korea remain substantially lower than the >90% rates reported in College of American Pathologists surveys. Increasing eGFR reporting rates is critical for improving renal care nationwide. According to KEQAS 2024 ABCr PT data, the CKD-EPI (2009) was the most widely used (39.2%), followed closely by the MDRD (IDMS-traceable) at 38.6% and the CKD-EPI (2021) at 21.0% (Fig. 2B). Since extensive research has validated the superiority of CKD-EPI equations over MDRD equations for clinical applications, laboratories still relying on the MDRD equation should transition to CKD-EPI to align with current standards. Alarmingly, seven laboratories reported using the non-IDMS-traceable MDRD equation, which is incompatible with standardized creatinine assays, necessitating immediate corrective action.

Until 2023, the MDRD remained predominant in Korea, with slight variation over time [6]. However, in late 2023, the Korean government revised national health screening guidelines (Ministry of Health and Welfare Announcement No. 2023-292), mandating the use of the CKD-EPI (2009) equation for eGFR calculations beginning in 2024. This policy shift prompted a rapid transition among laboratories, demonstrating the substantial influence of government mandates on clinical practices. Despite prior efforts by KSLM, KEQAS, and the Korean Society of Clinical Chemistry to promote updated eGFR equations, significant progress was achieved after this intervention. Similarly, mandating eGFR reporting alongside creatinine measurements is a promising strategy to further improve eGFR reporting rates.

The choice of eGFR equations significantly impacts clinical decisions, even with identical creatinine measurements. A unified equation is crucial for consistency; however, no consensus exists in Korea. Developing a Korean-specific equation is challenging, making the selection of a suitable international equation a practical alternative. However, limited mGFR measurements in Korea hinder multicenter validation of eGFR equations.

In summary, standardized creatinine assays became widely adopted in Korea by 2017. eGFR reporting rates remain lower than those in the US and Europe, which may improve with greater participation from small- and medium-sized institutions and government mandates. The 2009 CKD-EPI equation appears to be the most suitable for clinical laboratories in Korea.